A 90 day, Phase 3, Open Labeled Exploratory Study of RELiZORB to Evaluate Safety, Tolerability, and Nutrient Absorption in Children with Short Bowel Syndrome who are Dependent on Parenteral Nutrition

项目概要/摘要 短肠综合征（SBS）通常是由于大量小肠的损失， 消化吸收治疗包括高热量饮食和通过静脉喂养（即，肠胃外 营养或PN）等。许多患者由于肠道长度或功能减少而无法脱离PN。 长期PN患者经常发生严重代谢并发症、败血症、肝胆疾病 包括胆汁淤积和纤维化，并可发展为肝衰竭。全肠道喂养（肠内营养） 不加肠外营养是预防上述并发症的最佳方法。 SBS患者肠内给予长链甘油三酯，尤其是肝硬化患者 由于胆汁酸吸收不良，导致胶束形成减少， 脂肪消化。膳食脂肪不能被胆汁酸乳化，不能被脂肪酶作用， 以粪便的形式排出患者体内。转换为其他形式的脂肪，如中链甘油三酯（MCT）， 在胆汁酸或胰腺功能不全的患者中，不需要胶束进行吸收可能耐受性更好 但不是最佳的，因为它们增加了肠中的渗透负荷。这可能会增加大便的机会 此外，MCT不含必需脂肪酸（FA）。提供基本FA的能力 例如以不需要形成用于吸收的胶束的形式存在于肠内制剂中的那些， 将使SBS患者和不再依赖PN的患者获得充足的营养， 继续保持与他们接受大部分胃肠外营养时相同的生长轨迹。 RELiZORB是一种酶盒，与肠内营养管组串联连接，旨在模拟 胰脂肪酶的功能据推测，通过使用这种体外脂肪酶装置，肠内营养将是 更好地吸收，并且随着肠内自主性的增加，PN依赖性降低。该产品消除了 需要肠道乳化，消除了药物的风险，包括脂肪酶，允许吸收在 时间饮食进入肠道。该装置已被证明可以消化大多数肠内配方中>90%的脂肪。 这是一项3期、开放标签、单中心临床试验，旨在确定 RELiZORB酶药筒与肠内营养联合使用时，儿科患者每日使用90天的生物利用度 SBS受试者，年龄2 - 18岁，PN依赖。PN热量较基线的变化， 每周评估一次，将通过曲线下面积作为平均百分比增加或减少进行评价， 以95%的置信区间表示。治疗后出现的不良事件数量（百分比），级别 2或以上，以及生命体征异常、粪便量/频率变化、造口 输出，需要减少肠内喂养，尿液颜色，血液学和生化参数的变化将 制成表格。生长z评分、72小时粪便脂肪和脂肪吸收系数、血浆FA、PN的变化 还将描述容量、肠内/经口营养和PN断奶能力。

Project Summary/Abstract Short bowel syndrome (SBS) is often due to the loss of large amounts of small intestine that compromises digestive absorption. The treatments include a high-calorie diet and feeding through the vein (i.e., parenteral nutrition or PN), among others. Many patients cannot wean from PN due to reduced intestinal length or function. Patients on long-term PN frequently experience serious metabolic complications, sepsis, hepatic biliary disorders including cholestasis, and fibrosis and can progress to liver failure. Full intestinal feeding (enteral nutrition) without PN is the optimal way to prevent the above complications. Enterally administered long chain triglycerides in patients with SBS, especially those with hepatic dysfunction, are not well tolerated due to bile acid malabsorption, which leads to decreased micelle formation and fat digestion. The dietary fat is unable to be emulsified by the bile acids and acted on by lipases before exiting the patient as stool. Switching to other forms of fat such as medium-chain triglycerides (MCTs) that do not require micelles for absorption may be better tolerated in patients with bile acid or pancreatic insufficiency but are not optimal as they increase the osmotic load in the intestine. This may increase the chance of stool dumping; moreover, MCTs do not contain essential fatty acids (FAs). The ability to provide the essential FAs such as those present in enteral formulas in a form that does not require the formation of micelles for absorption, would allow patients with SBS and those who are no longer PN dependent to receive adequate nutrition and continue to maintain the same growth trajectory as when they received the majority of their nutrition parenterally. RELiZORB is an enzyme cartridge connected in-line with enteral feed tubing sets designed to mimic the function of pancreatic lipase. It is hypothesized that by using this external lipase device, enteral nutrition will be better absorbed, and PN dependence reduced as enteral autonomy is increased. This product eliminates the need for intestinal emulsification and eliminates the risk of drugs, including lipases, allowing absorption at the time the diet enters the gut. The device has been shown to digest >90% of fat in most enteral formulas. This is a phase 3, open label single center clinical trial to determine the safety, tolerability, and bioavailability of the RELiZORB enzyme cartridge with enteral nutrition when used daily for 90 days in pediatric subjects with SBS, aged 2 years – 18 years, who are PN dependent. The change in PN calories from baseline, assessed weekly, will be evaluated by area under the curve as a mean percentage increase or decrease and presented with a 95% confidence interval. The number (percent) of treatment-emergent adverse events, grade 2 or above, as well as the incidence of abnormalities in vital signs, changes in stool amount/frequency, ostomy output, the need to decrease enteral feeds, changes in urine color, hematology and biochemistry parameters will be tabulated. Changes in growth z-scores, 72-hour fecal fat and coefficient of fat absorption, plasma FAs, PN volume, enteral/oral nutrition, and ability to wean from PN will also be described.